We have recently identified B7-H1, a new member of the B7 costimulatory molecule family. Preliminary data from our laboratory demonstrated that B7-H1 engages a receptor of T cells to provide an initial signal for costimulation of T cell growth in vitro and promote cell-mediated and humoral immune responses to antigens in vivo. However, the majority of human cancers examined so far express high levels of B7-H1 and engagement of activated T cells by tumor-associated B7-H1 promotes programmed cell death. The overall goal of our study is to elucidate cellular and molecular mechanisms of B7-H1 in immune regulation and to manipulate this pathway for treatment of autoimmune diseases and cancers. The central hypothesis of this proposal is that B7-H1 regulates T cell responses in autoimmune diseases and cancers in a positive and negative fashion through different receptors. To test this hypothesis, we will use bioinformatics, expression cloning and mass spectrometry techniques to identify the novel receptor of B7-H1. In addition, we will utilize B7-H1 deficient and transgenic mouse models to elucidate immunological functions of B7-H1 in vivo. We will also evaluate the effect of B7-H1 in graft versus host disease (GVHD) models for potential treatment of autoimmune diseases. Finally, we will examine the mechanisms of tumor-associated B7-H1 in evasion of active and adoptive immunity in mouse tumor models. It is anticipated that these studies will provide a foundation for the development of new approaches for the prevention and immunotherapy of autoimmune diseases, transplantation rejection and cancers.